This transcript has been edited for clarity.
Javed Butler, MD, MPH, MBA, FACC: Greetings, and welcome to our discussion on obesity and heart failure. I'm Dr Javed Butler. I'm a cardiologist and a clinical trialist with Baylor Scott & White Health in Dallas, Texas.
Mikhail N. Kosiborod, MD, FACC: I'm Dr Mikhail Kosiborod. I'm a cardiologist and clinical trialist at Saint Luke's Mid America Heart Institute in Kansas City.
Butler: I am absolutely delighted to have this discussion with Dr Kosiborod on the issues pertaining to obesity and heart failure because, for one thing, our thought processes continue to evolve. We have some really exciting data that are coming out that were led by Dr Kosiborod, but also because not many people have thought about this cardiometabolic syndrome, obesity and heart failure, simultaneously as much as Dr Kosiborod has.
Let me start, Mikhail, with the first question. Historically speaking, some clinicians have questioned whether obesity is actually good for patients with heart failure. This has been a long debate — whether we should actively ask patients to lose weight.
Now, there is no debate that overweight patients tend to develop heart failure more often. That's not the point. The point is that, if you already have heart failure, patients with lower body weight tend to have a higher mortality rate, and those with higher body weight tend to a have lower mortality rate. Can you opine on this a little bit?
Kosiborod: Thanks, Javed, for bringing this up. This is what we've called the obesity paradox in heart failure. The premise of the paradox is, as you mentioned, that higher body mass index (BMI) seems to be associated with better likelihood of survival, and people who lose weight in the setting of heart failure tend to have higher risk for all-cause mortality than those that don't lose weight. This paradox has been shown in several epidemiologic studies going back more than 20 years.
It has caused a large amount of consternation in the heart failure community, where many heart failure cardiologists were actually quite reluctant to recommend weight loss, even to their patients with significant or severe obesity. It is true, if you look at those studies, that there appears to be an epidemiologic association between higher BMI and better survival.
There are two very important caveats. The first is that those studies were done in people with advanced heart failure, predominantly those with reduced ejection fraction, and not in all patients with heart failure. The second caveat, which is by far the most important one, is that those studies did not differentiate between intentional and unintentional weight loss.
If you think of any chronic disease — it doesn't have to be heart failure; think of cancer. If you have a patient with cancer who suddenly starts losing weight without instituting any lifestyle modifications, medications, or bariatric surgery, we know that's not a sign of good prognosis. That's true of any chronic disease. If you have spontaneous unintentional weight loss, that's a harbinger of a bad prognosis because that means the disease is progressing and you're not going to do very well.
The same, of course, is true in heart failure, especially advanced heart failure with reduced ejection fraction, which is the patient population where most of the studies were done. That's, of course, a critical flaw in those studies. At the same time, as you pointed out, we've had a large amount of epidemiologic data showing that obesity is a huge risk factor for the development of heart failure.
We also have data now which suggest that, at least in patients with heart failure and mildly reduced or preserved ejection fraction, visceral adiposity and obesity is also correlating significantly with greater symptom burden, greater physical limitations, and more severe effects of the disease on a day-to-day basis. That, of course, has been at odds with this obesity paradox.
Butler: Can you expand on that a little bit? I understand the intentional weight loss issue very well, but now the question is whether obesity is making heart failure worse. When you say that obese patients with heart failure have more symptoms and more shortness of breath, that could be simply attributed to obesity. Do you think that obesity or visceral adiposity actually makes heart failure worse?
Kosiborod: I think there is a large and growing body of data to clearly indicate that there are pathobiological mechanisms where obesity, visceral adiposity, insulin resistance, and all of the pathobiological and metabolic pathways that get set off by those root causes would, in fact, drive the development and progression of heart failure, especially of heart failure with preserved ejection fraction (HFpEF).
Let me take a step back and address how obesity can cause heart failure or promote the progression of heart failure, and, in fact, be the causative factor behind a greater burden of symptoms and physical limitations and worse quality of life, for example.
We know that as people gain weight, especially when they gain adipose tissue, there are certain things that happen. As body surface area increases, there is a commensurate increase in blood volume and plasma volume, for example. It's not just total blood volume; it's also what we call stressed blood volume. That's the blood volume that may not be in the circulatory space but in the periphery, but it gets mobilized with any kind of physical activity.
What we know, and I think many of us have experienced clearly in practice, is that we have patients who have shortness of breath with physical activity that may also be living with overweight or obesity, and often that gets ascribed to being deconditioned or having overweight or obesity. In fact, when we study these patients, what we find is that they may potentially have pulmonary hypertension at baseline.
If they don't, many of them have exercise-induced pulmonary hypertension, where the filling pressures may be normal at baseline, but when they do any kind of physical activity, the pulmonary pressures, filling pressures, may skyrocket with relatively little activity. It can be demonstrated with exercise echocardiography or with exercise in the catheterization lab when you do a right heart catheterization.
Yes, there is expansion of plasma volume, blood volume, and especially stressed blood volume that gets mobilized with physical activity. Of course, we also know that there is a correlation between obesity, visceral adiposity, and insulin resistance; and things like hypertension, structural heart abnormalities like left ventricular hypertrophy, and fibrosis, and when combined, they ultimately translate into the symptoms of heart failure that we're talking about.
As was well demonstrated in many of the studies that have been done, it's not just that people who have overweight or obesity are short of breath because of overweight or obesity. They have these pathophysiologic reasons behind it.
A New Therapeutic Strategy for HFpEF
Butler: Let me recap what you said. Obesity, epidemiologically, is associated with good outcomes and the pathophysiology of obesity, with bad outcomes. That's what we call equipoise, and when you have an equipoise, you need a clinical trial. Can you tell us about the hypothesis behind the STEP-HFpEF trial and what you found, and where is this field of obesity treatment in HFpEF going?
Kosiborod: These are, of course, very exciting times because now we have data not only from observational epidemiologic studies but also from clinical trials. The STEP-HFpEF program comprises two trials, STEP-HFpEF and STEP-HFpEF DM, the first of which has been presented and published so far. That's the one that I'm going to talk about. The second one is still in progress. [Editor's note: The results of STEP-HFpEF DM were presented at the American College of Cardiology Scientific Session 2024, after this video was recorded.]
The hypothesis behind the program was exactly what we just talked about. There was a large amount of data suggesting that obesity is common in people with HFpEF. One thing we didn't touch on is that the majority of patients who have HFpEF in the United States, and increasingly so globally, are living with overweight and obesity.
Many of us have felt for many years now that this is not an accident, but in fact, there is a reason the majority of patients with HFpEF are living with overweight and obesity. Obesity may in fact be what's causing heart failure in many of these patients.
If that hypothesis is correct, if obesity is not incidental, that it actually is a cause of heart failure in many of these patients, then what we need to do is prove in a randomized clinical trial that, by directly targeting obesity, we can improve those outcomes, including symptoms, physical limitations, and quality of life.
Until recently, we didn't have good pharmacologic tools to be able to produce clinically meaningful weight loss, but of course, that has changed now in the past few years with the advent of incretin-based therapies, especially GLP-1 receptor agonist-based treatments such as semaglutide.
The idea behind the STEP-HFpEF trial was that we were going to recruit patients with what we call obesity-related HFpEF, and we were going to randomly assign them to semaglutide at a weight loss dose of 2.4 mg once weekly, or matching placebo, and we were going to study those outcomes. That's exactly what we did.
We randomized patients with obesity-related HFpEF to semaglutide 2.4 mg once a week or matching placebo, and we treated them for 52 weeks. The dual primary endpoints in the trial were the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, which is a gold standard of assessing heart failure–related symptoms and physical limitations, and the second dual primary endpoint was a change in body weight between baseline and week 52.
There were a number of important secondary endpoints, including objective measures of exercise function, like 6-minute walking distance, as well as measures of inflammation. We also had some exploratory outcomes, like biomarkers of congestion, NT-proBNP, and adjudicated heart failure events.
What did we find? Patients treated with semaglutide had a much greater improvement in the heart failure–related symptoms and physical limitations as measured by the KCCQ clinical summary score. In fact, the KCCQ benefit was the largest that we've ever seen with any pharmacologic intervention in HFpEF to date. There was a more than 7-point improvement on average in the KCCQ clinical summary score. It was not just clinically meaningful, but also a highly statistically significant benefit.
We also saw, not surprisingly, a greater reduction in body weight with semaglutide vs placebo. There was a more than 20-meter improvement in the 6-minute walking distance test with semaglutide compared with placebo. Just for a frame of reference, that's roughly the improvement in 6-minute walking distance that you see with a supervised cardiac rehab program in patients with heart failure when studied in clinical trials.
There was improvement in a hierarchical composite endpoint that combined clinical events with things like KCCQ and 6-minute walking distance, and finally, a reduction in biomarkers of inflammation as well as biomarkers of congestion.
We had very few clinical events of heart failure hospitalizations and urgent visits, but they were very favorably distributed. Of 13 events, there was only one in the semaglutide group and 12 in the placebo group. Finally, semaglutide was very well tolerated, with significantly fewer serious adverse events than placebo.
All in all, there was a very favorable benefit-risk balance with semaglutide vs placebo in this patient population, which really opens up a whole new area, potentially, of efficacious treatments in people with obesity-related HFpEF. Of course, this was the first trial ever to study a pharmacologic agent specifically targeting obesity in this patient population.
Treating HFpEF Patients With Diabetes
Butler: Congratulations. I think this was big news. Other than SGLT2 inhibitors, we really don't have anything to treat patients with HFpEF, and these patients have a lot of residual risk. Why are you doing a separate trial of patients with HFpEF and type 2 diabetes?
Kosiborod: There are a number of different reasons. One is that, of course, these are the trials targeting obesity as a potential therapeutic strategy for HFpEF. We need to keep in mind that, in trials of antiobesity medications, people with type 2 diabetes tend to lose quite a bit less weight than those without type 2 diabetes. There are many potential theoretical reasons for that, which we are not going to get into right now, but it's just a simple fact. It doesn't matter which antiobesity drug you study.
We knew that there was a high likelihood that, in patients with diabetes, there would be less weight loss. We believe that weight loss is one of the reasons that we see benefits with semaglutide in this patient population.
Second, people with type 2 diabetes are treated differently. For example, in the era when we started these trials, people with diabetes were much more likely to receive SGLT2 inhibitors, than those without diabetes. There are also specific safety vulnerabilities in people with type 2 diabetes, like hypoglycemia or potential risk for progression of diabetic retinopathy or maculopathy, which is not really pertinent to people who don't have type 2 diabetes.
So, there are many different reasons to study these two patient populations separately and get a clear answer. The last thing I will mention is that people with type 2 diabetes also have a more severe phenotype of HFpEF than those without type 2 diabetes. We know that people with more severe phenotypes sometimes don't respond as well to treatments. Those were the key reasons why we did two separate trials.
Butler: Mikhail, thank you so much. It's always great to talk to you, and this was a great discussion. I learned a lot. Hopefully, it was of help to our listeners as well.
Kosiborod: Thanks, Javed. The good news is that there's going to be much more on this topic in the coming years. There are many things going on in the development of new pharmacologic agents for obesity management. I think many of these have promise, based on what we've seen from the STEP-HFpEF program, specifically, in managing obesity-related HFpEF. I think the future is very bright. Thanks to our audience.
© 2024 American College of Cardiology & Medscape
Cite this: Targeting Obesity to Improve HFpEF Outcomes - Medscape - May 10, 2024.
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